This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Huntington?s Disease (HD) is a fatal neurodegenerative disease, which results from a mutation in the gene encoding the Huntingtin protein. The mutant protein is cleaved into toxic fragments by a class of cysteine proteases called caspases. Individuals afflicted with the disease develop loss of motor control, personality changes, and dementia. The goal of this work aims to inhibit the cleavage of the mutant Huntingtin protein by caspase-2 and caspase-6 in order to validate these two enzymes as therapeutic targets and to identify compounds that attenuate the accumulation of toxic Htt fragments involved in the pathology of the disease. Compounds identified through high-throughput screenings will be characterized and validated by x-ray crystallography prior to the application in cell-based assays. The long-term goals of the project are to validate caspase-2 and caspase-6 as drug targets and develop cures for Huntington?s Disease.